Scientists Say They've Found Protein That Might Help Fight AIDS

Scientists said yesterday that they had identified an elusive substance that allows some people to remain healthy for many years after being infected by the virus that causes AIDS. The finding could lead to a new approach to fight the disease.

"This is not going to be the ultimate solution, but it's another weapon we can use in our arsenal against H.I.V.," said Dr. David Ho, director of the Aaron Diamond AIDS Research Center in New York, which reported the finding.

Dr. Ho said it was unclear how easily the discovery could be put to use in treatment. But it is significant, he said, because it largely solves a 16-year-old medical mystery.

The scientists said in a paper published on the Web site of the journal Science at www.sciencemag.org/ content/current/, that the long-sought factors are three small proteins known as alpha-defensins, that the body usually uses to help kill bacteria.

But some scientists who have also been searching for the proteins were unconvinced, saying either that the paper was erroneous or that the defensins were just part of the story.

"This is definitely not it," said Dr. Jay Levy of the University of California at San Francisco, who postulated in 1986 that a protective substance existed and has been searching for it. "Along the way, we've ruled out a lot of factors, including the defensins."

Dr. Robert C. Gallo, director of the Institute of Human Virology at the University of Maryland, said he and his colleagues had found two other protective substances that they have not published papers about.

"I would agree that it is very likely that they identified something that is correct," Dr. Gallo said of the Aaron Diamond researchers.

But he added that "it doesn't account for all" of the factor.

Dr. Robert I. Lehrer, a professor of medicine at the University of California at Los Angeles who led the discovery of human defensins in the 1980's, called the new work "a very exciting finding."

AIDS researchers have been intrigued that 1 to 5 percent of people infected by H.I.V. can live for 10 or 15 years or even longer with apparently no damage to their immune systems. The scientists call those untreated people long-term nonprogressors.

Dr. Levy first noticed that those patients had certain immune cells, CD8 T-cells, that seemed to produce a protective factor that he called CD8 antiviral factor, or CAF. Since then, people have been racing to identify which of the hundreds of proteins produced by the CD8 cells could be that factor.

In 1995, Dr. Gallo and colleagues identified a group of compounds, beta-chemokines, that suppressed some but not all the types of the virus. The Aaron Diamond scientists, led by Dr. Linqi Zhang, theorize that the defensins account for most of the rest of the protective factor.

The scientists searched for proteins produced by CD8 cells of three nonprogressors but not by the cells of four people became ill from the virus. They used a new technology, protein chips, developed by Ciphergen Biosystems, a biotechnology company in Fremont, Calif. The chips, slices of aluminum about the size of a stick of chewing gum, contain tiny spots of chemicals that stick to different types of proteins. That allows proteins to be sorted and fed into a mass spectrometer to determine their weight.

"Basically, we came at the old question with a new tool," Dr. Ho said.

The manager of the project for Ciphergen, Dr. Rebecca E. Caffrey, said previous techniques could not easily spot small, highly charged proteins like the defensins.

"They were looking all around," Dr. Caffrey said, "but they couldn't see them."

Dr. Caffrey and several other Ciphergen employees were co-authors of the paper. Ciphergen will own any patents resulting from the discovery. Dr. Caffrey said the company would not block research by others but would probably seek royalties on any drugs or diagnostic tests based on the discovery. Ciphergen will in turn pay a royalty to the Aaron Diamond center, which is affiliated with Rockefeller University.

Dr. Zhang and Ciphergen are working on a test to tell whether infected people will be nonprogressors by checking to see whether their CD8 cells make defensins.

Using defensins as a medicine might be difficult, in part because they are hard to manufacture, Dr. Ho said. But clues to treat AIDS might come from understanding how the defensins work, which is unknown.

Dr. Bruce Walker, director of the AIDS division at the Harvard Medical School, said defensins might not be that useful therapeutically because they appear to have only a "fairly modest" effect in suppressing the virus. Dr. Walker also said it was not clear that CAF is "the key pivotal factor accounting for nonprogression." Some people might withstand the virus because of genetic variations or because a weak virus infects them.

Defensins are produced in large quantities by white blood cells known as neutrophils that engulf bacteria and kill them. There has been some work showing that defensins also fight viruses, including H.I.V.

A co-discoverer of defensins, Dr. Michael E. Selsted of the University of California at Irvine, said the new paper might be flawed because the CD8 cells were grown in culture along with other white blood cells that are known to produce defensins. So the defensins might not be coming from the CD8 cells.

The Aaron Diamond scientists said if that were the case, they would have also found the defensins in the cells of those who did become ill from H.I.V. The researchers also said they had found defensins in cells of nonprogressors that were kept separate from other blood cells.

Another reason some experts questioned the findings is that most noninfected people appear to make defensins in their CD8 cells. That would suggest that most people should be nonprogressors, which is not the case. Dr. Ho, noting that the infected people who become sick were not producing defensins, said producing it might somehow be turned off in most infected people but not in the nonprogressors.